Extracellular signal regulated kinases, ERK1/2 and ERK5, are activated by asbestos fibers in mesothelial[unreadable] and airway epithelial cells and play critical roles in cell survival. ERK1/2-dependent Fra-1 expression is also[unreadable] linked causally to morphologic transformation of rat mesothelial cells and expression of genes (c-met, cd44)[unreadable] stimulating cell proliferation and migration. We hypothesize that activation of ERK1/2 and ERK5 signaling[unreadable] pathways occur by carcinogenic fibers (asbestos, erionite) in the pathogenesis of human malignant[unreadable] mesothelioma (MM) and are potentiated by SV40 in a co-carcinogenic manner. Recent exciting data also[unreadable] suggest that these survival pathways are activated in MMs after exposure to chemotherapeutic drugs and[unreadable] can be manipulated to achieve increased cell killing. Thus, we also hypothesize that ERK1/2 and ERK5[unreadable] pathways contribute, alone or cooperatively, to MM cell survival after chemotherapy. In Aim 1, we will test[unreadable] crocidolite and chrysotile asbestos, well-characterized Turkish erionite (see Project 1), and their nonfibrous[unreadable] analogs, alone and with co-exposures to SV40 to determine if ERK1/2, and ERK5 activity, fos/jun family[unreadable] members, and AP-1 transactivation correlate with patterns of transformation and carcinogenicity as[unreadable] determined in the in vitro/in vivo models developed by Dr. Carbone (Core C). In Aim 2, we will use a panel[unreadable] of SV40+ and - MMs from Core B to determine the effects of dominant negative constructs and small hairpin[unreadable] (sh) RNA interference (RNAi) vectors targeting ERK1/2 and ERK5 on parameters of in vitro cell[unreadable] transformation and survival after treatment with Carmustine (BCNU). In collaboration with Dr. Testa (Project[unreadable] 3) we will also determine if the AKT survival pathway is modified in these studies. In Aim 3, a mouse[unreadable] orthotopic model will be used to determine if SV40+ and - MMs stably transfected with shMEKI, shERKS or[unreadable] both constructs before intrapleural injection and administration of Carmustine, have altered growth and[unreadable] metastases. Identifying the pathways of cell survival in the pathogenesis of MMs is highly significant for[unreadable] prevention and treatment of these devastating tumors. This Program Project allows our previous[unreadable] mechanistic studies in rodent mesothelioma models to be validated in human mesotheliomas and provides[unreadable] us with expertise on virology and MM pathology (Dr. Carbone), AKT survival pathways (Dr. Testa) and use[unreadable] of normal human mesothelial and MM cells (Dr. Pass).